Locked-in Syndrome in a Nigerian male with Multiple Sclerosis: a case report and literature review.

Background Locked-in syndrome is an extremely difficult neurologic condition to recognize, especially by the non-specialists. A case of locked-in syndrome in a 41–year old Niger Deltan Nigerian with relapsing remitting form of multiple sclerosis (MS) is presented, including a detailed literature review. Patient and case report The patient was in a state of spastic quadriplegia, motionless and aphasic (mute), with the preservation of consciousness and the ability to open and blink the eyes and move them vertically. Two episodes of the disease, varying in duration, have been described. The diagnosis of MS was made from the history and the typical clinical presentation: history of relapsing and remitting signs and clinical evidence of multi-focal involvement of the central nervous system. Conclusion Patient died at the age of 45 years, from pulmonary complications. This article may enhance easy recognition and management of the syndrome by all clinicians.


Background
Locked-in syndrome (LIS) is a rare and difficult condition to recognize by clinicians, especially the non-neurologists.  This syndrome poses serious challenges to the clinicians both in terms of the diagnosis and management, for it may be confused with stroke and other causes of unconsciousness. To the non-specialist doctor the patient appears unconscious; such a belief may lead the clinician to a wrong diagnosis and inappropriate management of the patient, especially if the doctor fails to examine vertical ocular movements. Another danger is that the attending doctors and nurses may discuss the "unconscious" patient's condition at the bedside, to the hearing of the patient, which may enormously stress the patient and cause deterioration of the condition.
The syndrome is characterized by quadriplegia and anarthria in a patient with preserved consciousness: [2][3][4][5][6][7][8][9][10][11][12][13]. The patient is motionless and mute, but retains the ability to open and blink the eyes and move them vertically. The diagnosis in most cases, is made after a family member or hospital nursing staff calls the attention of the doctor to the fact that the patient, who appears comatose is awake and aware of his immediate surroundings or if MRI shows a ventral pontine lesion, coupled with a normal EEG in an otherwise unresponsive patient. It is known that cerebral infarction or haemorrhage, brainstem trauma, demyelinating disease, tumours and encephalitis [5-7;14] can cause LIS, especially when these lesions affect the ventral portion of the lower pons and medulla, although demyelinating diseases are rare in the African continent. The prevalence of MS is less than 1 per 100,000 in the equatorial area (e.g. Nigeria) and blacks are at lower risk than whites in all latitudes. There are no reports in the literature of LIS in an African with multiple sclerosis. We saw such a patient in our practice at the University of Calabar Teaching Hospital, Calabar, Nigeria, whom we followed-up until his death. We hereby report this interesting case, to enhance easy recognition of the syndrome by all clinicians, especially those practicing in developing countries.
Case report

The First Episode
A 41 -year old Nigerian male university lecturer was previously well until the day his wife first noticed some degree of unsteadiness in his gait, while walking. This did not bother him until about 2 months later when he complained of weakness in all four limbs. Days later, while waiting to address a conference, the weakness suddenly became so profound that someone else had to take-over the reading of his prepared conference The patient was in the motionless-mute state for 5 months. From the 6th-8th months, according to the wife, without further medical care, apart from occasional physiotherapy, functions gradually returned: initially movements in the upper limbs resumed, followed by ability to sit up and the use of his lower limbs. Later the speech gradually improved. About a year after the onset of illness, patient, not discouraged by residual neurologic deficits (namely, spastic gait and speech disorder) , resumed duty at his workplace.
A repeat neurological evaluation 7 months after he resumed duty revealed intact cognitive functions. However, he complained of unsteadiness in walking, hearing difficulty, with buzzing sound in both ears like the sound of an approaching aeroplane. He could not recall most of the events of the past months of his illness. On examination: mild quadriparesis with dysarthria; audiometric test: bilateral sensorineural deafness (worst on the left); fundoscopy: bitemporal pallor; computerized tomography (CT) of the brain showed slightly dilated lateral ventricles, without suggesting its definitive cause in this particular case: normal EEG.
The buzzing sounds in the ears cleared completely by the 21st month of illness; but hearing difficulty and unsteady gait persisted. Patient had to wear hearing aids.

Second Episode
In the 32nd month of illness, patient suffered yet another attack: unsteady gait, severe weakness of the four limbs and profound speech disturbance. Generally, the presentation reminded the family members of the 1st attack. Consequently the family once again called in the Pastor of his Church, for spiritual healing. Three weeks later, when patient's condition further deteriorated, he was brought to the hospital. Neurological evaluation revealed: dementia; a motionless patient, quadriplegic, unable to talk, sit-up or walk; painful flexor/extensor spasms; cranial nerves palsies (3rd, 6th and 7th). The relapsing nature of the disease, with symptoms/signs indicative of multi-focal central nervous system involvement, together with the failure of CT scan to identify lesion suggestive of pontine haemorrhage or infarction, tumour or brainstem trauma, raised the suspicion, that ventral pontine demyelination (multiple sclerosis) may be the most likely cause of our patient's Locked -in Syndrome, and that the attacks (episodes 1 and II) were exacerbation of the multiple sclerosis. Prompted by this realization, the management of the case was reviewed, and included (i) corticosteroid (prednisolone) therapy and (ii) Baclofen, for the treatment of spasticity and the painful flexor/extensor spasms. In the next two months, patient's condition gradually improved, the spasticity became less incapacitating with time. The speech too improved during the 2 -month stay in hospital. But in one occasion, patient's condition deteriorated drastically: for the first time, during the course of illness, he lost consciousness, for about 6 hours. Investigations revealed; (i) normal chest x-ray (excluded pneumonia) and (ii) asexual P. falciparum parasitaemia (confirmed severe malaria as the trigger for the deterioration of the patient's condition). Patient responded dramatically to a course of anti-malaria drug therapy (with fansidar): regained full consciousness within 12 hours. Satisfied with the level of improvement of his mental state, motor function and speech, patient was discharged home by his doctors, at the end of a 2-month stay in the hospital. By the 4th month, the patient had recovered most functions and was well again.

Death of Patient
8 months after discharge from hospital, patient's condition once again deteriorated: at first he was febrile; and later became quadriplegic and comatous. He was rushed to a nearby private hospital, where chest x-ray examination revealed pneumonia. Before appropriate antibiotic therapy could be initiated the patient died. The family did not allow autopsy.
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Case Definition
Emile Zola, [15] a non-medical writer, was the first in 1868, to describe a woman with this syndrome in a book "Therese Raquin". However, it was more than hundred years later that Plum and Posner [16] introduced the term "Locked-in Syndrome".
LIS was first re-defined in 1966 as quadriplegia, lower cranial nerve paralysis and mutism, with preservation of consciousness, vertical gaze and upper eyelid movements [16]. So that mutism would not be mistaken for unwillingness to speak, [17] in 1986, LIS was again re-defined as a syndrome characterized by quadriplegia and anarthria, with preservation of consciousness. [18] The locked-in patient is usually conscious, while lying mute and motionless. He retains blinking and voluntary vertical eye movements, which facilitate non-verbal communication [1][2][3][4][5][6][7][8][9][10][11][12][13][14]19]. That means, the patient is aware of his surroundings, but is physically locked-in. [12,13] Some cases may exhibit decerebrate posturing. [6] One could logically refer to this state as akinetic mutism since the patient is akinetic (motionless) and mute, but this condition originally coined by Cairns [12], is somewhat different in that the lesion of akinetic mutism lies in the cerebral hemispheres hence the patient is unaware of his surrounding but shows sleepwake-cycle and may be able to withdraw from a painful stimulus.

Pathologic Basis of LIS
The pathophysiology of LIS involves a lesion affecting the ventral portion of the lower pons or medulla with the sparing of the upper pontine tegmentum. [6;14] The diencephalons and the ascending reticular formation responsible for consciousness lie above the mid pons hence consciousness is preserved in these patients. Thrombosis of the upper segment of the basilar artery resulting in infarction, haemorrghage, trauma (brainstem contusion or vertebro-basilar axis dissection), viral brainstem encephalitis, central pontine myelinolysis, demyelinating disease (acute or chronic relapsing multiple sclerosis), and primary and secondary tumours, all affecting the ventral pons or medulla, are the usual causes of lockedin syndrome [2,[6][7][8][9]13,14]. There are reports also, that severe Guillian Barre Syndrome [20] and snakebite [21;22] may cause LIS.
A lesion at the mid pontine level, while sparing the somatosensory pathways, may interrupt [2][3][4][5]17,18,23,24] the corticobulbar and corticospinal tracts to the lower cranial nerves and the limbs, resulting in the paralysis of all four limbs, face and pharynx and larynx. The bilateral facio-glossopharyngo-laryngeal paralysis [25] causes anarthria, dysphagia and limits the use of the muscles of facial expression in communication [2]. These factors may explain why the locked-in patient is motionless, quadriplegic and mute, but conscious, as it was the case with our patient.
Vertical eye movements are controlled from a centre in the superior collicular region of the midbrain and are thus preserved together with the pupillary light reflex [13]. A mid pontine lesion is likely to affect the abducens nucleus and cause the loss of lateral gaze, which is a feature of the disease as manifested in this case. The preserved partial eye control can therefore be utilized to affirm awareness in the patient by ordering him to open and close the eyes. This patient also experienced buzzing sound in both ears, which took more than two years to clear, and sustained a permanent hearing defect in both ears. These auditory disturbances may suggest pontine auditory hallucinosis (i.e. complex auditory illusions with some qualities of hallucination, which may accompany pontine lesion). Auditory hallucinosis consists of alternating musical tones, like an organ or a jumble of sound (like a symphony Orchestra tuning up) or siren-like or buzzing sound, like a swarm of bees.
These auditory sense disturbances are more complex than neurosensory tinnitus but less formed than temporal lobe hallucinations. They are usually associated with impairment of hearing in one or both ears and other neurologic signs related to the pontine lesion (as in our patient).
Brainstem evoked potentials may reveal intact cochlear, auditory nerve and cochlear nuclear responses, although our patient showed a bilateral sensorineural deafness.
The mild dilatation of the lateral ventricles in this case may indicate some degree of obstruction of the ventricular system; but we cannot use this to explain LIS in our patient as the computerized tomography did not suggest the actual cause of this dilatation and there was no history to suggest tumour or support a vascular aetiology (cerebral haemorrhage or infarction) of LIS in our patient.

Locked -In Syndrome
The diagnosis of LIS [1,2,5,33], in most cases, is made when family members or hospital nursing staff call the attention of doctors to the fact, that the patient, who appears comatous, is awake and aware of his immediate surroundings or if MRI shows a ventral pontine lesion, coupled with a normal EEG, in an otherwise unresponsive patient. In such cases, it is mandatory for the doctor to assess voluntary eye opening and blinking abilities and vertical eye movements [6]. These brainstem-mediated movements are preserved in LIS. CT scanning, MRI and auditory evoked response are some of the sensitive tests that can be used to investigate the brainstem of LIS patient. Unfortunately, we did not have these facilities in our practice. A conventional EEG with stimulation can distinguish between LIS (normal EEG, as it was with our patient) and coma (abnormal EEG).

Multiple Sclerosis (MS)
Initially the MS patient presents with an unsteady gait, spastic paraparesis, retrobulbar neuritis, diplopia and sphincter dysfunction [6,14].All or most symptoms may disappear after a few days/weeks/months. Our patient presented with most of these initial symptoms. Infections, trauma or pregnancy can trigger exacerbation of this disease. Diagnosis of MS is based on the total clinical picture that indicates the involvement of different parts of the central nervous system (CNS) at different times. [6,14] The multiple CNS lesions in MS are detectable by electrocerebral responses evoked by: (i) monocular visual stimulation with checkerboard patterns (visual evoked potentials, VEP); monaural stimulation with repetitive clicks (brainstem auditory evoked potentials, BAEP); and electrical stimulation of a peripheral nerve (somatosensory evoked potentials, SSEP) [6;19]. MRI too has become nearly indispensable in confirming the diagnosis of MS [6]. These facilities were not available for the management of our patient.
The Cerebro-Spinal Fluid (CSF) is commonly abnormal [6]: mild lymphocytosis or slightly increased protein concentration, especially soon after an acute relapse. Spinal tap was not done, because the relations did not create the opportunity for us to do this relatively simple procedure. CSF protein electrophoresis could have shown the presence of discrete bands in the 1gG region (oligoclonal bands), as this is the case in 90% of MS Patients [6]. The prevalence [7] of MS is less than 1 per 100,000 in the equatorial (e.g. Nigeria).There is increasing risk of development of MS with increasing latitude. Blacks are at lower risk than whites at all latitudes. From the history, it was known that our patient once lived in Britain for several years.
Whether this had anything to do with the development of MS in our patient was difficult to establish.

Multiple Sclerosis
The fact that MS is undoubtedly a rare disease in the African continent (and as the probable cause of LIS in our patient) makes this case very interesting. Clinically, MS can take any of the following forms: [6,7,20]

Prognosis
LIS mortality is about 60%, greatest in the first 4 months of illness, higher (70%) in patients with vascular lesion than non-vascular causes (40%) [5].Ten year survivor rates as high as 80% have been reported [2]. Even limited physical recovery can improve quality of life and enable the patient to return to live with their families. Early multidisciplinary [3,5,[17][18][19][20][21][22][23][24] rehabilitation and effective nursing care reduces mortality from acute LIS. [3] Young patients survive better. Survivors may recover partially or completely over a period of weeks or months. The following are some possible causes of death of LIS patients; • Pulmonary complications are the leading causes of death e.g. aspiration of saliva, due to dysphagia and impaired cough reflex leads to atelectasis and pneumonia. Immobility predisposes to pulmonary embolus [32].
• Death from primary destructive lesions (the lesion that caused the syndrome): cerebral infarction, haemorrhage, demyelination, trauma, encephalitis, all involving the ventral pons and sparing the tegmentum. Our patient died from pulmonary complication (pneumonia).
Prognosis: most patients die within a few weeks or months. A few remain locked-in for over a year before gradually recovering [5].

Conclusion
We have presented here a case of locked-in syndrome in a Nigerian male with multiple sclerosis. The patient lies motionless and mute, yet conscious. The patient with the complete syndrome signals that he or she is conscious by opening and blinking the eyes and moving them in the vertical plane. Many clinicians have difficulty recognizing the syndrome while evaluating the "unconscious" patients, because they fail to routinely assess vertical eye movement and the patient's ability to open and blink the eyes. Diagnosis is often made after patient's family members or nursing staff call the attention of the doctor to the fact that the motionless and mute patient is in fact conscious and aware of his or her Page number not for citation purposes 8 surrounding. The fact that our patient's LIS was probably caused by a demyelinating disease (multiple sclerosis), a condition that is rare among blacks and in the African Continent made this case very interesting.
We do hope that our case report and the detailed literature review will further enhance easy recognition and management of the syndrome by all clinicians, especially those in Africa.